Chemokine receptor genotype is associated with diabetic nephropathy in Japanese with type 2 diabetes.

Kunihiro Nakajima,Takeshi Ogihara,Ken Sakai,Takashi Nomiyama,Yasushi Tanaka,Tomio Onuma,Ryuzo Kawamori,Lianshan Piao

doi:10.2337/diabetes.51.1.238

Abstract

Glomerular infiltration of monocytes/macrophages occurs in diabetic patients with nephropathy, and chemokine receptor signals are thought to play a key role in the development of nephropathy. Recently, polymorphism of the chemokine receptor (CCR)2 coding region V64I and the CCR5 promoter region 59029 (G/A) have been identified. Accordingly, we evaluated the effects of these genotypes on diabetic nephropathy. CCR2 V64I and CCR5 59029 (G/A) were detected by polymerase chain reaction-restriction fragment-length polymorphism in 401 patients with type 2 diabetes who had a serum creatinine <2.0 mg/dl. Although the CCR2 V64I genotype showed no association with nephropathy, the frequency of the CCR5 59029 A-positive genotype (G/A or A/A) was significantly higher in patients with microalbuminuria (urinary albumin-to-creatinine ratio [ACR] > or = 30 and <300 mg/gCre, 86%) and patients with macroalbuminuria (ACR > or = 300 mg/gCre, 87%) than in patients with normoalbuminuria (ACR <30 mg/gCre, 75%; P = 0.0095). Polytomic logistic regression analysis showed that the CCR5 59029 A-positive genotype was associated with nephropathy (odds ratio 2.243, P = 0.0074). These results suggest that the CCR5 promoter 59029 A genotype may be an independent risk factor for diabetic nephropathy in patients with type 2 diabetes.

Highlights

Glomerular infiltration of monocytes/macrophages occurs in diabetic patients with nephropathy, and chemokine receptor signals are thought to play a key role in the development of nephropathy
Monocyte/macrophage infiltration has been detected in the glomeruli of rats with streptozotocin-induced diabetes and in renal biopsy specimens from patients with diabetic nephropathy, suggesting that the secretion of chemokines is enhanced in diabetes and that monocyte recruitment to
Because the major receptor for monocyte chemoattractant protein 1 (MCP-1) and RANTES expressed on the surface of monocytes is chemokine receptor (CCR)[2] and CCR5, respectively, CCR2- and CCR5-mediated monocyte recruitment and differentiation to macrophages in the glomerulus may play a key role in diabetic nephropathy (3,4)

Summary

Brief Genetics Report

Kunihiro Nakajima,[1] Yasushi Tanaka,[1] Takashi Nomiyama,[1] Takeshi Ogihara,[1] Lianshan Piao,[2] Ken Sakai,[1] Tomio Onuma,[1] and Ryuzo Kawamori[1]. ACR, albumin-to-creatinine ratio; CCR, chemokine receptor; CVD, cardiovascular disease; IL-1␤, interleukin-1␤; IMT, intima-media thickness; MCP-1, monocyte chemoattractant protein 1; PCR, polymerase chain reaction; RANTES, regulated upon activation, normal T-cell expressed and secreted; RFLP, restriction fragment–length polymorphism; SNP, single-nucleotide polymorphism; TNF-␣, tumor necrosis factor-␣. The G-to-A substitution leads to replacement of valine by isoleucine at amino acid 64 (CCR2 V64I) in the first transmembrane domain of CCR2, and the 46295A genotype (CCR2 64I) has been reported to show an association with the progression of AIDS and with the development of sarcoidosis Another SNP, G/A at nucleotide position 59029 in the promoter region of CCR5 (G59029A), has been recently identified (13).

Stage of nephropathy

CHEMOKINE RECEPTOR GENOTYPE

Odds ratio

Findings

RESEARCH DESIGN AND METHODS